Racemization process for alpha-amino-caprolactam and lysine amide

ABSTRACT

1. IN A METHOD FOR THE RACEMIZATION OF OPTICALLY ACTIVE MATERIAL OF THE GROUP CONSISTING OF A-AMINOCAPROLACTAM AND LYSINE AMIDE AND MIXTURES THEREOF BY HEATING IN THE PRESENCE OF A STRONG BASE, THE IMPROVEMENT WHICH COMPRISES EMPLOYING ANHYDROUS AMMONIA AS SOLVENT AND HEATING SAID MATERIAL IN SOLUTION THEREIN AT CONCENTRATION OF AT LEAST 10 PERCENT BY WEIGHT.

United States Patent Claims ABSTRACT OF THE DISCLOSURE Anhydrous ammonia is employed as a racemization solvent for optically active a-amino lactams and amino acid amides. Concentrated solutions can be obtained and the solvent can be readily removed from the product for recycle.

This is a continuation of application Ser. No. 165,379, filed July 22, 1971, now abandoned.

This invention relates to the racemization of optically active amides of amino acids and aminolactams. More particularly, this invention relates to an improved process for the racemization of optically active amides of amino acids and aminolactams in the presence of a strong base.

I BACKGROUND OF THE INVENTION It is known that the racemization of optically-active aminolactams and amides of amino acids can be carried out in the presence of sodium by distillation in the absence of a solvent under vacuum at elevated temperatures, e.g., 180 to 190 C. This process has the disadvantage that high temperatures must be employed and only about 70% recovery is obtainable, greatly adding to the expense of such process. Racemization of aminolactams by heating with sodium hydroxide in the presence of organic solvents, such as toluene and other hydrocarbons, is also known, and is disclosed in U.S. Pat. 3,105,067. This process has the disadvantage that the comparatively high boiling point of the solvent makes it difficult to obtain a solvent-free product and adds to the heat requirements needed to recover the solvent for recycle. These add greatly both to the capital investment and the operating costs of such process.

SUMMARY OF THE INVENTION DETAILED DESCRIPTION OF THE INVENTION The process of the invention is of particular interest for the racemization of lysine amide and u-aminocapro lactam. Either the D or L optically active forms can be employed as starting materials in the present process.

Patented Oct. 15, 1974 Strong bases suitable for use in the invention include the alkali and alkaline earth metal salts including their hydroxides, such as potassium hydroxide, sodium hydroxide and the like; carbonates, such as sodium carbonate, calcium carbonate and the like; oxides, such as calcium oxide, magnesium oxide and the like; amides, such as sodium amide, lithium amide and the like; alcoholates such as sodium methoxide, potassium ethoxide and the like; and quaternary ammonium compounds, such as tetrabutyl ammonium hydroxide, tetraisopropyl ammonium hydroxide and the like. The amount of base employed is not critical, however generally from about 0.2 to about 4% by weight of the starting material of the base will be employed.

The amount of the anhydrous ammonia employed in the present process is not critical. However excellent results are obtained in concentrated solutions containing up to about 40% by weight of the amide of the amino acid or aminolactam starting material at room temperature. Generally from about 1 to 40% by weight solutions can be employed, and preferably from about 10 to 30% by weight of the amide of the amino acid or aminolactam in ammonia will be employed.

The temperature of reaction can range up to the decomposition temperature of the starting materials, but generally temperatures from about 50 C. up to about 200 C. will be suitable. Preferred temperatures of to 140 C. are generally employed. The time required for reaction will vary but is readily determinable by one skilled in the art and will depend on the amino acid amide or aminolactam starting material to be racemized, the temperature of reaction, and the concentrations of the starting material and of the catalyst in ammonia. Under optimum conditions periods up to about 10 hours will be adequate for complete racemization.

The invention will be further illustrated by the following examples, but it is meant to be understood that the invention is not to be limited to the details disclosed therein. In the examples, percentages and parts are by weight.

Thin layer chromatograms were developed using as solvent 25 parts by glyme to 6 parts of concentrated aqueous ammonia. The chromatograms were visualized with UV light and Ninhydrin.

The degree of racemization was determined by comparing the optical rotation, measured in a l N hydrochloric acid solution of the racemized product, with the known value for the fully resolved amino acid amide or aminolactam.

EXAMPLE 1 Into a Paar-type reactor fitted with a stirrer were charged 0.505 part of L-lysineamide and 0.030 part of sodium amide. The reactor was cooled to about 20 C. by a Dry Ice-acetone bath and 13.1 parts of anhydrous ammonia were added. The reactor was then immersed in an oil bath maintained at C. and reaction continued for 8 hours while stirring. The reactor was then cooled, vented and the product collected. The reactor was rinsed with 1 N aqueous hydrochloric acid and the combined solutions filtered.

The product had a [m1 of +4.16. [a] for L- lysineamide is ;+18.6, indicating 22.3% optical activity and that about 78% racemization had occurred. Only a single spot was obtained on a thin layer chromatogram.

EXAMPLES 2-4 l The procedure of Example 1 was followed except that different catalysts, reaction temperatures and concentraare summarized in Table I below.

TABLE I Example number 2 3 4 Charge (parts):

L-lysineamide 0. 502 0. 5006 1. 0053 Sodium amide 0. 033 sodium hydroxide- 0. 020. 0. 040 anhydrous ammonia" 15. 5 15. 5. 0 Conditions:

Temperature, C 110 100 v100 Reacticn time, hours. 8.0 8. 0 8. 0 Percent concentration l 3. 13 3. 22 16. 67 Optical activity of product, [Q19 +3. 18 +0. 4 +1. 6 Percent racerniZation 3 98 91 Thln layer chromatogram, spots '1 1 EXAMPLE Into a glass-lined autoclave fitted witha stirrer were charged 0.9986 part of L-a-aminocaprolactam and 0.026 part of sodium methoxide. The autoclave was sealed,

flushed with nitrogen, cooled to -60 C. and five parts of ammonia were added. The reactor was immersed in an oil bath maintained at 100 C.:5 C. and reaction continued for four hours while stirring. The reactor was then cooled to about 60 C., the ammonia distilled off and the product collected.

The product had a of +0.25. [M for L-ocaminocaprolactam is 34.0, indicating that about 100% racemization had occurred. Only a single spot was obtained on a thin layer chromatogram.

EXAMPLES 6-9 The general procedure of Example 5 was followed except varying the catalyst, concentration and reaction time. Reaction conditions and results are summarized in Table II below.

TABLE 11 Example number 6 7 8 9 Charge (parts):

L-a-aminocaprolactam 1. 0253 1. 0000 1. 0186 1. 0038 Sodium hydroxide 0. 028 0. 017 0. 006 0. 0047 Anhydrous ammonia-.. 5. 8 6. 0 6. 0 6. 0 Conditions:

Reaction time, hours. 4 4 4 2 Percent, concentration 15. O 14. 3 14. 3 14. 3 Optical activity of product 0. 49 0.00 0. 00 7. 26 Percent racemization 99 100 100 Thin layer chromatogram, spots 1 1 1 1 Trace of lysine.

EXAMPLE 10 This example is given for purposes of comparison to.

The procedure Example 5 was followed charging l.ll86 parts of L-a-aminocaprolactam, and 5.8 parts of ammonia and reacting for four hours at C.

The product had an [M of -33.2 indicating that little, if any, racemization had taken place.

We claim:

1. In a method for the racemization of optically active material of thegroup consisting of a-aminocaprolactam .and lysine amideand mixtures thereof by heating in the presence. of a strong base, the improvement which comprises employing anhydrous ammonia as solvent and heating said material in solution therein at concentration of at least 10 percent byfweight.

2. A methodaccording to claim 1 wherein the temperature is maintained between about 75 and about 3. A method according to claim 2 wherein the starting material is a-aminocaprolactam.

4. A method according to claim 2 wherein the starting material is lysine amide.

5. A method according to claim 2 wherein from 0.2 to 4% by weight of the starting material of the strong base is employed.

6. In a method for the racemization of optically active a-aminocaprolactam or lysineamide by heating in the presence of a strong base, the improvement which comprises dissolving the starting material in anhydrous ammonia in concentration of fromlO to 40 percent by weight of the solvent and maintaining the temperature between about 50 C. and about 200 C.

7. A method according to claim 5 wherein the strong base is sodium hydroxide.

References Cited UNITED STATES PATENTS 3,024,231 3/1962 Scherrer 260-239.3 R 3,105,067 9/1963 Nelemans et a1. 260239.3 R 3,692,775 9/1972 Kubanek et a1... 260-239.3 R

OTHER REFERENCES Audrieth et al.: Non-Aqueous Solvents, (Wiley) (1953), pp. 4348.-

JOHN D. RANDOLPH, Primary Examiner R. T. BOND, Assistant Examiner US. Cl. X.R. 260-561 A 212 UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No. 38u2O73 Dated October 5, 1974 j 6 Inventor(s) R. Fuhrmann, F. W. Koff and S Sifniades It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:

Column 2, line M1 "by" should read of Column 1, claim 6 line 5 1O to 40" should read 10 to 30 o Signed and Sealed this twenty-third 0f March 1976 [SEAL] Arrest:

RUTH C. MASON C. MARSHALL DANN Arresting Officer Commissioner ofPatenls and Trademarks 

1. IN A METHOD FOR THE RACEMIZATION OF OPTICALLY ACTIVE MATERIAL OF THE GROUP CONSISTING OF A-AMINOCAPROLACTAM AND LYSINE AMIDE AND MIXTURES THEREOF BY HEATING IN THE PRESENCE OF A STRONG BASE, THE IMPROVEMENT WHICH COMPRISES EMPLOYING ANHYDROUS AMMONIA AS SOLVENT AND HEATING SAID MATERIAL IN SOLUTION THEREIN AT CONCENTRATION OF AT LEAST 10 PERCENT BY WEIGHT. 